digitoxin and Brain-Neoplasms

Malignant glioma is one type of common malignancy in central nervous system (CNS) tumors which has a very bad influence on the survival quality of the patients. In this regard, lots of studies on improving the therapeutic effects of malignant glioma have been done continuously. This study takes glioma stem cells (GSCs) as the subject and focuses on the sensitization effect of digitoxin (DT) on the apoptosis mediated by TNF-related apoptosis-inducing ligand (TRAIL) to prove that the combination therapy of DT and TRAIL has a more active effect of inducing GSCs apoptosis. This study used cultured GSCs. Comparisons of single drug therapy and combination therapy indicated that DT had a synergistic action with TRAIL to produce a more active effect of inducing the apoptosis of GSCs. This effect was also shown in the changes of expressions of cell apoptosis pathway related protein markers tested by Western Blot method. In conclusion, DT had a sensitization effect on GSCs apoptosis mediated by TRAIL.

Topics: Apoptosis; Brain Neoplasms; Digitoxin; Drug Therapy, Combination; Glioblastoma; Humans; Neoplastic Stem Cells; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured

Glioblastoma multiforme is the most lethal and aggressive astrocytoma among primary brain tumors in adults. However, most glioblastoma cells have been reported to be resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Here, we have shown that digitoxin (DT), a clinically approved cardiac glycoside for heart failure, can induce TRAIL-mediated apoptosis of glioblastoma cells. DT in noncytotoxic doses (20 nmol/l) can increase TRAIL-induced apoptosis in TRAIL-resistant U87MG glioblastoma cells. Treatment with DT led to apoptosis and a robust reduction in the levels of the antiapoptotic protein survivin by inducing its proteasomal degradation; however, it did not affect the levels of many other apoptosis regulators. Moreover, silencing survivin with small interfering RNAs sensitized glioma cells to TRAIL-induced apoptosis, underscoring the functional role of survivin depletion in the TRAIL-sensitizing actions of DT. We demonstrate that inactivation of survivin and death receptor 5 expression by DT is sufficient to restore TRAIL sensitivity in resistant glioma cells. Our results suggest that combining DT with TRAIL treatments may be useful in the treatment of TRAIL-resistant glioma cells.

Topics: Apoptosis; Brain Neoplasms; Caspases, Effector; Caspases, Initiator; Cell Line, Tumor; Digitoxin; Down-Regulation; Drug Resistance, Neoplasm; Enzyme Activation; Glioblastoma; Humans; Inhibitor of Apoptosis Proteins; Receptors, TNF-Related Apoptosis-Inducing Ligand; RNA, Small Interfering; Survivin; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation